Opioid receptors play an important role in the regulation of the immune response to a number of infectious agents, and a major part of this regulation involves changes in the expression and the functional activity of certain chemokine receptors. Specifically, our results show that the activation of the ?-opioid receptor induces a significant increase in the level of expression of CCR5 and CXCR4 in both monocytes and T cells. In contrast, activation of the ?-opioid receptor has the opposing effect. In addition, we fid that both the ?- and ?- opioid receptors regulate the functional activity of these chemokine receptors, through the process of heterologous desensitization. We have reported results which show that the opioid-induced cross- desensitization of CCR5 and CXCR4 results in the loss of HIV-1 co-receptor activity. We have now reported the biochemical characterization of the signaling pathway that is responsible for the cross-desensitization of CCR5, and these studies have provided the basis for additional studies which form the present grant proposal. In this proposal we intend to characterize the biochemical basis for the loss of co-receptor function for both CCR5 and CXCR4 following heterologous desensitization. We will test the hypothesis that the activation of ?- opioid receptor results in critical changes at the level of the cytoskeleton which are required as a part of the early events following HIV-1 infection. We also propose to assess the influence of the opioid-induced cross- desensitization on the capacity of monocytes to traffic across the blood-brain barrier, using a well characterized in vitro model system. Finall, we will assess the capacity of chronic in vivo opioid administration to mediate cross-desensitization of CCR5 using a non-human primate model system. We believe the proposed studies should provide a greater understanding of the influence of opioids on the neuroinflammation associated with HIV infection, and in addition, may offer potential therapeutic targets for treatment or prevention of the HIV- associated neuropathogenesis. PUBLIC HEALTH RELEVANCE: Opioid drug abuse is responsible for greater susceptibility to infection with a variety of human pathogens, including the Human Immunodeficiency Virus (HIV). This project addresses the influence of opioids on the expression and function of critical chemokine receptors, including the major HIV co-receptors. This project investigates the ability of opioid receptors to influence susceptibility to HIV infection, and focuses in part on the development of strategies which may lead to novel antiviral therapeutic agents.